PROJECT SUMMARY Ischemic stroke affects 700,000 individuals annually in the U.S. and is the leading cause of long-term disability in adults. Current acute stroke treatment paradigms (i.e., reperfusion therapies) are not widely applicable to most patients due to a very narrow therapeutic window. New approaches that can be offered acutely to the majority of ischemic stroke patients, and continued throughout the duration of post-stroke care, can limit stroke severity, can complement or even enhance rehabilitation, and could transform ischemic stroke recovery. The treatment of obstructive sleep apnea (OSA) among patients with acute ischemic stroke represents one such novel therapeutic approach. The Recovery In Stroke Using PAP (RISE-UP) study is a randomized controlled trial among 180 patients with acute ischemic stroke and moderate/severe OSA diagnosed by ambulatory polysomnography comparing PAP treatment with usual care over 6 months. The randomization scheme will be 1:1:1 (n=60 acute intervention: n=60 subacute intervention: n=60 control/usual care). Acute intervention patients will start PAP within 1-week post stroke symptom onset, and subacute patients will start PAP 1-month post symptom onset. Both groups will continue PAP therapy through the duration of the study, reinforced with technical assistance and behavioral support. All patients will receive a healthy lifestyle education intervention focused on secondary stroke prevention. The primary outcome is functional stroke recovery at 6 months as measured by the Modified Rankin Scale (mRS). Secondary outcomes measures include stroke severity (NIHSS), the Berg Balance Scale, falls, actigraphic measures of motor activity, symptom measures of sleepiness (ESS), vitality (SF-36), depression (PHQ-9), cognition (MoCA), and quality of life measures (SSQOL, SAQLI). The Specific Aims: (1) Test whether a PAP treatment for OSA in ischemic stroke improves stroke severity, post-stroke physical activity, post-stroke symptoms, and stroke functional recovery (primary outcome). (2) Determine whether acute vs subacute initiation of PAP in ischemic stroke results in greater improvement in post-stroke outcomes (stroke severity, physical activity, symptoms, stroke recovery). (3) Conduct qualitative, in depth, interviews with 25-30 stroke patients, the family members, and acute care providers to elicit their experience with PAP use, including factors that influence adherence. Exploratory Aim: Evaluate whether polysomnographic measures have prognostic utility in understanding the variability in stroke recovery. This work will be accomplished by an experienced multidisciplinary team of investigators (sleep medicine, nursing, neurology, respiratory therapy, physiatry, and behavioral science) and will fulfill a critical step towards developing new clinical practice pathways that involve treating OSA in ischemic stroke and developing more personalized approaches for post-stroke care and PAP management.